The broad goal of the computational core is to support the cell biology, molecular biology, biochemistry, crystallography, and medicinal chemistry components of the program project towards cures for Chagas' disease, malaria, African sleeping sickness, and leishmaniasis. The targets are cysteine proteases in Trypanosoma cruzi, Plasmodium falciparum, Trypanosoma brucei, and Leishmania major, respectively. Bioinformatics, comparative protein structure modeling, and computational docking will contribute to target discovery, lead discovery, and lead optimization. In particular, computing will be applied to the discovery of potential target cysteine proteases, their protein inhibitors, and drug-like compounds. The specific aims are: (i) to identify all putative papain-like cysteine proteases in the genomes of T. cruzi, P. falciparum, T.brucei, and L. major, (ii) to identify all putative protein inhibitors of the target cysteine proteases; (iii) to suggest small inhibitors that are suitable as lead compounds for drug development against parasite cysteine proteases; (iv) to support the iterative process of lead optimization for a small number of leads against a small number of protease targets, including cruzein, rhodesain, and falcipains 2 and 3. The proposed computations are timely due to the confluence between the availability of the genomic sequences, protein structures, computing capabilities, and advances in methods for comparison of protein sequences, protein structure modeling, and ligand docking.